8-[3-(6-Fluoro-1,2-benzisoxazol-3-yl)propyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one

ABSTRACT

Novel 8-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-1-phenyl-1,2,8-triazaspiro[4.5]decan-4-ones, process for the preparation thereof, and methods of treating psychoses and alleviating pain employing compounds and compositions thereof are described.

DESCRIPTION OF THE INVENTION

The present invention relates to novel8-[3-(1,2-benzisoxazol-3-yl)propyl]-1-phenyl-1,3,8-triazaspiro-[4.5]decan-4-ones.More particularly the present invention relates to8-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-onesof formula 1 ##STR1## wherein R is hydrogen or loweralkyl; X ishydrogen, loweralkyl, loweralkoxy, halogen or trifluoromethyl; orpharmaceutically acceptable acid addition salts thereof, which areuseful for treating psychoses and alleviating pain, alone or incombination with inert psychoses treating and pain alleviatingadjuvants.

Preferred8-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-onesare those wherein R is hydrogen.

As used through the specification and appended claims, the term "alkyl"refers to a straight or branched chain hydrocarbon radical containing nounsaturation and having 1 to 7 carbon atoms such as methyl, ethyl,1-propyl, 2-propyl, 1-butyl, 1-pentyl, 2-pentyl, 3-hexyl, 4-heptyl andthe like; the term "alkoxy" refers to a monovalent substituent whichconsists of an alkyl group linked through an ether oxygen and having itsfree valence bond from the ether oxygen such as methoxy, ethoxy,propoxy, butoxy, 1,1-dimethylethoxy, pentoxy, 3-methylpentoxy,2-ethylpentoxy and the like; the term "halogen" refers to a member ofthe family consisting of chlorine, fluorine, bromine or iodine. The term"lower" as applied to any of the aforementioned groups refers to a grouphaving a carbon skeleton containing up to and including 5 carbon atoms.

The compounds of the present invention which lack an element of symmetryexist as optical antipodes and as the racemic forms thereof. The opticalantipode may be prepared from the corresponding racemic forms bystandard optical resolution techniques, involving, for example, theseparation of diastereomeric salts of those instant compoundscharacterized by the presence of a basic amino group and an opticallyactive acid, or by the synthesis from optically active precursors.

The present invention comprehends all optical isomers and racemic formsthereof. The formula of the compounds shown herein are intended toencompass all possible optical isomers of the compounds so depicted.

The novel8-[3-(6-flouro-1,2-benzisoxazol-3-yl)propyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-onesof formula 1, the compounds of the present invention, are prepared bycondensing 3-(3-chloropropyl)-6-fluoro-1,2-benzisoxazole of formula 2##STR2## the synthesis of which is described in U.S. Patent ApplicationSer. No. 257,698, filed Apr. 27, 1981, with readily available1-phenyl-1,3,8-triazaspiro[4.5]decan-4-ones of formula 3. ##STR3##wherein R is hydrogen or loweralkyl; and X is hydrogen, loweralkyl,loweralkoxy or trifluoromethyl. The condensation is convenientlyperformed by treating the halide 2 with the piperidine 3 in the presenceof an acid acceptor, a displacement promotor and a suitable solvent.Among acid acceptors, there may be mentioned alkali metal carbonates andalkali metal bicarbonates such as, for example, lithium carbonate,sodium carbonate and potassium carbonate, and lithium bicarbonate,sodium bicarbonate and potassium bicarbonate. Potassium carbonate andsodium bicarbonate are preferred. Among displacement promotors, theremay be mentioned alkali metal halides such as, for example, sodiumiodide and potassium iodide, and sodium bromide and potassium bromide.Potassium iodide is preferred. Among suitable solvents, there may bementioned polar aprotic substances such as, for example,dimethylformamide, dimethylacetamide and hexamethylphosphoramide.Dimethylformamide is preferred. The temperature at which thecondensation is conducted is not narrowly critical. It is desirable,however, to perform the condensation at a temperature within the rangeof about 50° C. to about 130° C. to assure a reasonable rate ofconversion. A reaction temperature within the range of about 70° C. to110° C. is preferred.

The8-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-onesof the present invention are useful as analgesic agents due to theirability to alleviate pain in mammals which is demonstrated in thephenyl-para-quinone writhing assay in mice, a standard assay foranalgesia [Proc. Soc. Exptl. Biol. Med., 95, 729 (1953)]. Presented inTable I is the analgesic activity of a representative compound of theinvention and two standards, expressed as the estimated subcutaneousdose at which the phenyl-para-quinone induced writhes are reduced by 50%in mice, i.e. the ED₅₀ -value.

                  TABLE 1                                                         ______________________________________                                                           Analgesic Activity                                         Compound           (ED.sub.50 mg/kg)                                          ______________________________________                                        8-[3-(6-fluoro-1,2-benzisoxazol-                                              3-yl)-1-phenyl-1,3,8-triazaspiro-                                             [4.5]decan-4-one hydrocholoride                                                                  5.7                                                        propoxyphene       3.9                                                        pentazocin         1.3                                                        ______________________________________                                    

Analgesia production is achieved when the present8-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-onesare administered to a subject requiring such treatment as an effectiveoral, parenteral or intravenous dose of from 0.01 to 100 mg/kg of bodyweight per day. A particularly effective amount is about 25 mg/kg ofbody weight per day. It is to be understood, however, that for anyparticular subject, specific dosage regimens should be adjustedaccording to the individual need and the professional judgment of theperson administering or supervising the administration of the aforesaidcompound. It is to be further understood that the dosages set forthherein are exemplary only and that they do not, to any extent, limit thescope or practice of the invention.

The8-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-onesof the present invention are useful for treating psychoses by virtue oftheir ability to block apomorphine-induced climbing in mammals.

Antipsychotic activity is determined in the climbing mice assay by amethod similar to those described by P. Protais et al.,Psychopharmacol., 50, 1 (1976) and B. Costall, Eur. J. Pharmacol., 50,39 (1978).

The subject CK-1 male mice (23-27 grams) are group-housed under standardlaboratory conditions. The mice are individually placed in wire meshstick cages (4"×4"×10") and are allowed one hour for adaptation andexploration of the new environment. Then apomorphine is injectedsubcutaneously at 1.5 mg/kg, a dose causing climbing in all subjects for30 minutes. Compounds to be tested for antipsychotic activity areinjected intraperitoneally 30 minutes prior to the apomorphine challengeat a screening dose of 10 mg/kg.

For evaluation of climbing, 3 readings are taken at 10, 20 and 30minutes after apomorphine administration according to the followingscale:

    ______________________________________                                        Climbing Behavior     Score                                                   ______________________________________                                        Mice With:                                                                    4 paws on bottom (no climbing)                                                                      0                                                       2 paws on the wall (rearing)                                                                        1                                                       4 paws on the wall (full climb)                                                                     2                                                       ______________________________________                                    

Mice consistently climbing before the injection of apormorphine will bediscarded.

With full-developed apomorphine climbing, the animals are hanging ontothe cage walls, rather motionless, over longer periods of time. Bycontrast, climbs due to mere motor stimulation usually only last a fewseconds.

The climbing scores are individually totaled (maximal score: 6 per mouseover 3 readings) and the total score of the control group (vehicleintraperitoneally--apomorphine subcutaneously) is set to 100%. ED₅₀values with 95% confidence limits are calculated by a Linear RegressionAnalysis. Antipsychotic activity expressed as the ED₅₀ value of arepresentative8-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-1-phenyl-1,3,8-triazaspiro-[4.5]decan-4-oneas well as two standard antipsychotics are presented in Table II.

                  TABLE II                                                        ______________________________________                                                           Antipsychotic Activity                                     Compound           ED.sub.50 (mg/kg)                                          ______________________________________                                        8-[3-(6-fluoro-1,2-benzisoxazol-                                              3-yl)propyl]-1-phenyl-1,3,8-                                                  triazaspiro[4.5]decan-4-one                                                   hydrochloride      0.10                                                       haloperidol (standard)                                                                           0.11                                                       sulpiride (standard)                                                                             4.5                                                        ______________________________________                                    

Antipsychotic activity is achieved when the present8-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-oneare administered to a subject requiring such treatment as an effectiveoral, parenteral or intravenous dose of from 0.01 to 50 mg/kg of bodyweight per day. A particularly preferred effective amount is about 25mg/kg of body weight per day. It is to be understood, however, that forany particular subject, specific dosage regimens should be adjusted tothe individual need and the professional judgment of the personadministering or supervising the administration of the aforesaidcompound. It is to be further understood that the dosages set forthherein are exemplary only and they do not, to any extent, limit thescope or practice of the invention.

Compounds of the invention include:

a.8-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one;

b.8-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-1-(4-methylphenyl)-1,3,8-triazaspiro[4.5]decan-4-one;

c.8-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-1-(2-methylphenyl)-1,3,8-triazaspiro[4.5]decan-4-one;

d.8-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-1-(4-chlorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one;

e.8-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-1-(3-trifluoromethylphenyl)-1,3,8-triazaspiro[4.5]decan-4-one.

Effective amounts of the compounds of the invention may be administeredto a subject by any one of various methods, for example, orally as incapsule or tablets, parenterally in the form of sterile solutions orsuspensions, and in some cases intravenously in the form of sterilesolutions. The free base final products, while effective themselves, maybe formulated and administered in the form of their pharmaceuticallyacceptable addition salts for purposes of stability, convenience ofcrystallization, increased solubility and the like.

Preferred pharmaceutically acceptable addition salts include salts ofmineral acids, for example, hydrochloric acid, sulfuric acid, nitricacid and the like, salts of monobasic carboxylic acids such as, forexample, acetic acid, propionic acid and the like, salts of dibasiccarboxylic acids such as, for example, maleic acid, fumaric acid, oxalicacid and the like, and salts of tribasic carboxylic acids such as, forexample, carboxysuccinic acid, citric acid and the like.

The active compounds of the present invention may be administeredorally, for example, with an inert diluent or with an edible carrier.They may be enclosed in gelatin capsules or compressed into tablets. Forthe purpose of oral therapeutic administration, the aforesaid compoundsmay be incorporated with excipients and used in the form of tablets,troches, capsules, elixirs, suspensions, syrups, wafers, chewing gumsand the like. These preparations should contain at least 0.5% of activecompound, but may be varied depending upon the particular form and mayconveniently be between 4% to about 75% of the weight of the unit. Theamount of present compound in such composition is such that a suitabledosage will be obtained. Preferred compositions and preparationsaccording to the present invention are prepared so that an oral dosageunit form contains between 1.0-300 mgs of active compound.

The tablets, pills, capsules, troches and the like may also contain thefollowing ingredients: a binder such as microcrystalline cellulose, gumtragacanth or gelatin; and excipient such as starch or lactose, adisintegrating agent such as alginic acid, Primogel, corn starch and thelike; a lubricant such as magnesium stearate or Sterotes; a glidant suchas colloidal silicon dioxide; and a sweetening agent such as sucrose orsaccharin or a flavoring agent such as peppermint, methyl salicylate, ororange flavoring may be added. When the dosage unit form is a capsule,it may contain, in addition to materials of the above type, a liquidcarrier such as a fatty oil. Other dosage unit forms may contain othervarious materials which modify the physical form of the dosage unit, forexample, as coatings. Thus tablets or pills may be coated with sugar,shellac, or other enteric coating agents. A syrup may contain, inaddition to the active compounds, sucrose as a sweetening agent andcertain preservatives, dyes and colorings and flavors. Materials used inpreparing these various compositions should be pharmaceutically pure andnon-toxic in the amounts used.

For the purposes of parenteral therapeutic administration, the activecompounds of the invention may be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of theaforesaid compound, but may be varied between 0.5 and about 50% of theweight thereof. The amount of active compound in such compositions insuch that a suitable dosage will be obtained. Preferred compositions andpreparations according to the present invention are prepared so that aparenteral dosage unit contains between 0.5 to 100 mgs of the activecompound.

The solutions or suspensions may also include the following components:a sterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl parabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parenteral preparationcan be enclosed in ampoules, disposable syringes or multiple dose vialsmade of glass or plastic.

The following Example is for illustrative purposes only and are not tobe construed as limiting the invention.

EXAMPLE 18-[3-(6-Fluoro-1,2-benzisoxazol-3-yl)propyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-onehydrochloride

To 35 ml of dimethylformamide was added 2.3 g of1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one, 2.5 g of3-(3-chloropropyl)-6-fluoro-1,2-benzisoxazole, 10 g of milled anhydrouspotassium carbonate, and a few crystals of potassium iodide. Afterstirring at 80° C. for two hrs, the mixture was filtered and thefiltrate evaporated to an oil. The oil was stirred with water and thenextracted into ether/ethyl acetate. The organic layer was washed withwater (2×), saturated sodium chloride solution and dried over anhydrousmagnesium sulfate. After filtering, the filtrate was treated withethereal hydrogen chloride, and the resultant precipitate was collectedand dried to yield 2.7 g (61%) of product, mp 230° C. (dec).Recrystallization from ethyl acetate/methanol gave the analytical samplemp 250° C.

ANALYSIS: Calculated for C₂₃ H₂₅ FN₄ O₂.HCl: 62.08%, 5.89% H, 12.59%:Found: 62.26%, 6.03%, 12.70%.

We claim:
 1. A compound of the formula ##STR4## wherein R is hydrogen orloweralkyl; X is hydrogen, loweralkyl, loweralkoxy, halogen ortrifluoromethyl; the optical antipods thereof, or pharmaceuticallyacceptable acid addition salts thereof.
 2. A compound according to claim1 wherein R is hydrogen.
 3. The compound according to claim 2 which is8-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one.